The broad long-term objective of the proposed study is the development of new chelating agents which are superior to any previously reported for the reduction of renal and hepatic levels of cadmium in rodent models. Our goal is to obtain compounds which are effective, in rodents, when at a level of 40 mu mol/kg and which remove renal and hepatic cadmium without causing any transport of cadmium to the brain or any increase in the cadmium content in any other organ. We have already developed compounds which are effective when administered at a level of 2OOmu mol/kg. From previous results the most promising group of compounds to pursue in these studies are the dithiocarbamates, which we have already shown to possess most of the desired properties; vicinal dithiols will also be examined, though these are a somewhat less promising group. These compounds are to remove cadmium from the kidneys in such a manner that, when starting with kidneys which exhibit dysfunction due to accumulated cadmium (100-200 ppm), a return toward more normal renal function will be facilitated. We plan to search for structure-activity relationships involving the newly prepared compounds in aft to assist in the development of optimally effective cadmium mobilizing agents. Such relationships will be sought for each of the major organs from which cadmium mobilization occurs and will include the determination of reasonably complete dose-response curves for the most potent of the compounds prepared. The optimum type of molecular structure needed to remove cadmium from each of the major individual organs which accumulate cadmium will also be examined, as present evidence indicates that these may differ significantly. It is also planned to examine several aspects of the basic mechanism of the cadmium mobilization process in order to determine how it might be most effectively accelerated, ie. via the use of adjuvants etc. These mechanistic studies will involve NMR studies of cadmium exchange processes similar to or identical with those which occur in vivo.